PARP1 (poly-ADP ribose polymerase-1) is an enzyme that participates in a variety of DNA-related functions including cell proliferation, differentiation, apoptosis, and DNA repair. PARP1 consumes NAD+ and ATP, which can culminate in cell dysfunction or necrosis. PARP1-induced necrosis has been implicated in cancer, stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP1 over-expressions has been correlated with endometrial cancer, BRCA-mutated ovarian cancer, BRCA-mutated serous ovarian cancer, and a number of other cancers, including neuroblastoma, testicular and other germ cell tumors, Ewing's sarcoma, malignant lymphoma, breast cancer, colon cancer, and tyrosine kinase-activated leukemia.
Thus, PARP1 is a therapeutic target for a variety of serious conditions including various types of cancer and neurodegenerative diseases.
CDKs (cyclin-dependent kinases) are a family of enzymes that play an important role in the regulation of the cell cycle. Progression through the cell cycle is governed by a series of checkpoint controls, otherwise referred to as restriction points, which are regulated CDKs. In turn, the CDKs are regulated at many levels, for instance by binding to cyclins. Checkpoint controls are defective in tumor cells due, in part, to disregulation of CDK activity. For example, altered expression of Cyclin E and CDKs has been observed in tumor cells, and deletion of the CDK inhibitor p27 KIP gene in mice has been shown to result in a higher incidence of cancer, such as breast cancer.
Thus, both PARP1 and CDKs are involved various diseases, including cancer. Dual inhibitors of PARP1 and CDK of the present invention have not been heretofore disclosed.